Acrylic latexes of methyl methacrylate, ethyl acrylate, and methacrylic acid have been used in milkcan linings and paper coatings in the food-packaging industry since about 1950, and such dispersions were specified in the U.S. Federal Register for food additives in 1961. Copolymers of ethylacrylate and methacrylic acid for enteric coatings were developed by Lehmann and Dreker in "Anwendung wassriger Kunststoffdispersioner zum uberzieken von Arzneiformen," Pharm. Inc., 34, 894-899 (1972).
Ethyl acrylate-methacrylic acid latexes can be prepared by emulsion polymerization. The emulsion polymerization mechanism of acrylate monomers with a hydrophilic methacrylic acid co-monomer is described by N. Sutterlin in "Structure/Property of Emulsion Polymers," Makromol. Chem. Suppl. 10/11, 403-418 (1985). For pharmaceutically useful polymethacrylates, the polymerization mechanism is described by K. Lehmann in "herstellung von Acrylharz-Filmtableten mit gesteuerter Winkstoffabgabe nach verschiedenen Spruhverfahren," APV-Informationdienst 18(1), 48-60 (1972).
Methacrylic acid-ethyl acrylate copolymer for enteric coatings is defined in U.S.P. XXII/NF XVII, U.S. Pharmacopeial Convention, Inc., 1990, as USP Methacrylic Acid Copolymer-Type C.
A 30% aqueous dispersion of the copolymer of ethyl acrylate and methacrylic acid is commercially available from Rohm GmbH, Darmstadt, Germany, under the tradename EUDRAGIT.RTM. L30D and is manufactured by emulsion polymerization of about 1:1 mole-ratio of methacrylic acid and ethyl acrylate; sodium lauryl sulfate and polysorbate 80 are used as the emulsifiers. The initiators are generally peroxygen compounds, which are chemically bonded to the polymers and are normally not found in substantial amounts in the final latex. The residual monomers can be either reduced or even eliminated by optimizing the polymerization process or by final steam distillation. Total residual monomer content in commercial EUDRAGIT.RTM. products is generally below 0.3%; normally less than 0.1% is found.
Effectiveness of a methacrylic acid-ethyl acrylate enteric polymer for coating of tablets generally depends on the rate of film forming during the coating of the tablet and the development of the cohesives film strength. When a methacrylic acid-ethyl acrylate emulsion polymer is used for enteric coating of pharmaceutical dosage forms, the polymer particles are deposited from an aqueous dispersion of discrete polymer spheres. Individual submicrometer-size spheres, each containing hundreds of polymer chains, coalesce into a continuous film as the water evaporates.
Kast describes the film formation mechanism for linear, non-crosslinking polymer particles in Makromol. Chem. Suppl. 10/11, 447 (1985). The film formation mechanism can be divided into three phases:
a) evaporation of water or drying; PA1 b) coalescence and deformation of latex particles; and PA1 c) cohesive strength development by the further gradual coalescence of adjacent latex particles and the interdiffusion of polymer chains from adjacent particles. PA1 Drugs and the Pharmaceutical sciences, vol. 36: Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited by J. M. McGinity, Marcel Dekker Inc, New York, N.Y., 1989. PA1 Handbook of Pharmaceutical Excipients, Published by American Pharmaceutical Association, Washington, D.C., 214 (1986). PA1 J. A. Seitz, "Aqueous Film Coating", Encyclopedia of Pharmaceutical Technology, vol. 1, edited by J. Swarbrick and J. Boylan, 337 (1988). PA1 G. S. Banker and G. E. Peck, "The New, Water-Based Colloidal Dispersions," Pharmaceutical Technology, 5(4), 55-61 (1981). PA1 R. E. Pondell, "From Solvent to Aqueous Coatings," Drug Development and Industrial Pharmacy, 10(2), 191-202 (1984). PA1 M. B. Davis, G. E. Peck, and G. S. Banker, "Preparation and Stability of Aqueous-Based Enteric Polymer Dispersions" Drug Development and Industrial Pharmacy, 12(10), 1419-1448 (1986). PA1 F. Gumowski, E. Doelker, and R. Gurny, "The Use of a New Redispersible Aqueous Enteric Coating Material," 11(2), 26-32 (1987 ). PA1 R. K. Chang, C. H. Hsiao, and J. R. Robinson, "A Review of Aqueous Coating Techniques and Preliminary Data on Release from a Theophylline Product," 11(3), 56-68 (1987). PA1 1. A coating system which employs a solution of coating polymer in a mixed organic and aqueous solvent system such as hydroxypropyl methylcellulose (HPMC) in ethanol/water. This method only partially eliminates the need for organic solvents. PA1 2. A coating system which employs an aqueous solution of water-soluble film-forming polymer. This method is limited to water-soluble polymers such as methylcellulose (MC), hydroxypropyl cellulose (HPC), and HPMC. Another limitation is the need to remove a large amount of water during drying and coating processes. PA1 3. A coating system which employs an aqueous solution of alkali salt of an enteric polymer such as sodium or ammonium salt of hydroxypropyl methylcellulose phthalate (HPMCP), polyvinylacetate phthalate (PVAP), or cellulose acetate phthalate (CAP). PA1 4. A coating system which employs the pseudolatex of a water-insoluble film-forming polymer. Pseudolatex is an aqueous colloidal dispersion of polymer which is, for practical purposes, indistinguishable from a true latex. However, it is prepared by employing a mechanical method of converting a pre-existing water-insoluble polymer into an aqueous colloidal dispersion. PA1 5. A coating system which employs a true latex of film-forming polymer prepared by emulsion polymerization of acrylic or methacrylic monomers. PA1 "This latex technology has become a complex empirical art. Subtle modifications in the composition of the recipes or in the method of synthesis can cause commercially significant changes in the end products obtained from vinyl-type or ethylenic monomers."
A conceptual visualization is depicted by Daniels et al., in Progress in Organic Coatings, 19, 359-378 (1991), as a latex dispersion consisting of spheres that are suspended and separated by electrostatic repulsion. As water evaporates, interfacial tension between water and polymer pushes particles into point contact in a close-packed ordered array. A strong driving force is necessary to overcome repulsive forces, deform the particles, and cause the spheres to fuse, thereby resulting in complete coalescence. Capillarity caused by the high interfacial surface tension of water provides the driving force to fuse the particles, and plasticizer inclusion in the dispersion swells and softens the polymer spheres, thereby facilitating coalescence and reducing minimum film-formation temperatures.
The polymer spheres are pulled closer together as a result of surface tension (water-air interfacial tension) or capillarity as the surrounding water film constricts. Energy required for the coalescence of spheres results from the surface tension of the polymer generated by the negative curvature of the particle surface and according to Dillon et al., in J. Colloid Science, 6, 108(1951) may be described by Frenkel's equation: ##EQU1## where .theta. is one-half the angle of coalescence (contact angle) at time t; .gamma. is the surface or interfacial tension, r is the radius of a sphere and .eta. is the viscosity of the spheres.
This equation illustrates the inverse relationship between internal viscosity (.eta.) of the spheres and the driving force (.gamma.) necessary to fuse or coalesce discrete particles. Further, it is evident that smaller-radius polymer spheres require less driving force (capillarity) to completely fuse or coalesce.
On the microscopic or molecular level, once the polymer particles are in contact with one another, molecular interdiffusion of macromolecules from one particle into its neighbor occurs, and their entanglement takes place. The formation of entanglements between polymer chains of adjacent particles is crucial to the development of mechanical strength of the resulting films. Generally, higher molecular weight polymer chains develop better entanglement and, as a result, cohesive strength.
Thus an effective methacrylic acid-ethyl acrylate enteric polymer should ideally have smaller particle size and adequate lower molecular weight polymer chains for rate of film forming, and also have a small portion of slightly higher molecular weight polymer chains for developing cohesive film strength.
The use of EUDRAGIT.RTM. L30D for the enteric coating of tablets has been described by Lehmann in Acta Pharmaceutica Technologica, 31, 96-106 (1988); Dechesne et al. in J. Pharm. Belg. 37, 273-282 (1982); Belanger et al. in U.S. Pat. No. 5,047,258 (1991) and Patell et al. in U.S. Pat. No. 4,775,536 (1988).
It is generally believed that the consistency during the coating process and thereby the coating performance of a waterborne acrylate enteric coating on tablets is not fully satisfied. It would thus be desirable to develop an improved polymeric composition which will reduce the batch to batch variation.
Further, because the enteric polymers are subjected to mixing and mechanical shear throughout coating of pharmaceutical forms process, it would thus be desirable to develop a process for making enteric polymers with improved shear stability. Enteric polymers with improved shear stability are more user friendly during coating and will not plug the coating line during a coating process of pharmaceutical forms.
Film coatings are applied to pharmaceutical dosage forms to 1) facilitate the swallowing of the dosage form, 2) control the release of the drug by either protecting the drug from the gastric environment of the stomach or reducing potential gastric irritation caused by high localized drug concentration, 3) protect the drug from the storage environment, 4) improve the appearance, and 5) mask undesirable tastes, odors, and colors. Coatings are commonly applied from organic solutions of various polymers such as cellulose acetate phthalate (CAP) and hydroxypropyl methylcellulose phthalate (HPMCP). Because of environmental concerns and the increase in cost of suitable solvents, it is desirable to apply coating compositions via an aqueous medium.
An enteric coating is defined in USP XXII as a coating which is intended to delay the release of the medication until the dosage form has passed through the stomach. Enteric coated tablets are thus one type of delayed release dosage forms.
The following references provide general background information on enteric coating methodology:
The common methods of eliminating or minimizing organic solvents in a coating process for preparing pharmaceutical dosage forms include the following:
U.S. Pat. No. 4,017,647 teaches a method for providing enteric coatings on solid pharmaceutical dosage forms in which enteric coatings are provided on solid dosage forms by coating the dosage forms with an aqueous solution of a polymeric substance having carboxyl groups in a water-soluble salt form and bringing thus coated dosage forms into contact with an inorganic acid to convert the polymeric substance into the acid form, which is insoluble in water.
U.K. Patent Application GB No. 2,057,876 teaches a method of preparing coated medicament-containing cores of a solid unit dosage form with an enteric coating. The coating was applied (e.g., in a coating pan) onto the medicament cores from an aqueous solution of a water soluble salt of a cellulose partial ester of a dicarboxylic acid, the aqueous solution being free from organic solvent, until an enteric coating around each medicament core had been built up. The salt may be a sodium or ammonium salt of HPMCP or CAP.
U.S. Pat. No. 4,177,177 teaches a polymer emulsification process comprising intimately dispersing a liquified water insoluble polymer phase at a certain viscosity in an aqueous liquid medium phase (at a certain ratio and temperature) containing at least one non-ionic, anionic, or cationic oil-in-water emulsifying agent at a certain concentration in the presence of an emulsion stabilizer at a certain concentration selected from the group consisting of those hydrocarbons and hydrocarbyl alcohols, ethers, alcohol esters, amines, halides, and carboxylic acid esters which are inert, nonvolatile, water insoluble, liquid, and contain a terminal aliphatic hydrocarbyl group of at least about 8 carbon atoms and mixtures thereof, and subjecting the resulting crude emulsion to the action of comminuting forces sufficient to enable the production of an aqueous emulsion containing polymer particles averaging less than 0.5 micron in size. This patent teaches that the disclosed polymer emulsification process is carried out at a temperature of about 40.degree. C. to 90.degree. C.
U.S. Pat. No. 4,330,338 teaches a coating composition for pharmaceutical dosages. The dosages use a set of FDA-approved polymers with a long history of pharmaceutical and food use. Pseudolatices containing such polymers are used to produce soluble, enteric, or sustained release coatings when the formulations are applied to dosage forms. Various other ingredients besides the polymers are taught to be required in the coating composition.
U.S. Pat. No. 4,462,839 teaches a process for making a polymeric powder which is readily dispersible in water to provide a composition useful for forming an enteric coating on pharmaceutical dosage forms, comprised of treating a freshly prepared spherical water-insoluble enteric polymer particles with a phosphate salt in an amount sufficient to minimize coalescence of particles during spray drying. U.S. Pat. No. 4,518,433 teaches a similar process except that acetylated monoglyceride is added to the dispersion before spray drying to produce the water-redispersible powder.
U.S. Pat. No. 5,025,004 discloses a process for preparing polymeric compositions which are suitable for coating medicaments or for use in cosmetic formulations and the novel compositions prepared therefrom. The process makes stable, colloidal, latex-like dispersions of coating polymers which can be readily dried to form polymeric powder materials. The process makes use of a novel combination of a water-in-oil emulsifier and an oil-in-water emulsifier.
Emulsion polymerization is a complex empirical art since it usually involves more than four ingredients and often more variations in reaction conditions. J. Gardon wrote the following in "Emulsion Polymerization," in High Polymers, Vol. 29, Wiley, N.Y., 143 (1977):
Copolymers having a wide range of complicated structures for varying applications may be prepared through process design and choice of ingredients such as monomers, initiators, emulsifiers, and chain transfer agents in a emulsion polymerization. The final properties are greatly influenced by the choice of emulsifiers, the choice of initiators, the choice of other ingredients, the reaction temperature, and the method of monomer addition.